Received: 21 October 2019 

|
  Revised: 7 February 2020 
|  Accepted: 13 February 2020

DOI: 10.1111/epi.16469

FULL -LENGTH ORIGINAL RESEARCH

A retrospective comparison of phenobarbital and levetiracetam

for the treatment of seizures following cardiac surgery in
neonates

Céline Thibault1   | Maryam Y. Naim1   | Nicholas S. Abend1,2   | Daniel J. Licht2   |

J. William Gaynor3   | Rui Xiao4  | Shavonne L. Massey2

1
Department of Anesthesiology and Critical
Care Medicine, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania
2
Departments of Neurology and Pediatrics,
Children’s Hospital of Philadelphia,
University of Pennsylvania, Philadelphia,
Pennsylvania
3
Division of Cardiothoracic Surgery,
Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania
4
Department of Biostatistics, Epidemiology,
and Informatics, University of Pennsylvania
School of Medicine, Philadelphia,
Pennsylvania
Correspondence
Shavonne L. Massey, Division of
Neurology, Children's Hospital of
Philadelphia, Philadelphia, PA 19104.
Email: masseysl@email.chop.edu
Funding information
National Institute of Neurological Disorders
and Stroke, Grant/Award Number: NS-
072338 and NS-096058; Wolfson, Grant/
Award Number: NS-072338
Abstract
Objective: To compare the safety and efficacy of phenobarbital and levetiracetam in
a cohort of neonates with seizures following cardiac surgery.
Methods: We performed a retrospective single-center study of consecutive
neonates with electrographically confirmed seizures managed with antiseizure
medication after cardiac surgery from June 15, 2012 to December 31, 2018. We
compared the safety and efficacy of phenobarbital and levetiracetam as first-line
therapy.
Results: First-line therapy was phenobarbital in 31 neonates and levetiracetam in
22 neonates. Phenobarbital was associated with more adverse events (P = .006).
Eight neonates (14%) experienced an adverse event related to phenobarbital use,
including seven with hypotension and one with respiratory depression. No ad-
verse events were reported with levetiracetam use. The cessation of electrographic
seizures was similar in both groups, including 18 neonates (58%) with seizure
cessation after phenobarbital and 12 neonates (55%) with seizure cessation after
levetiracetam (P = 1.0). The combined cessation rates of phenobarbital and lev-
etiracetam when used as first- or second-line therapy were 58% and 47%, respec-
tively (P = .47).
Significance: Phenobarbital was associated with more adverse events than lev-
etiracetam, and the two drugs were equally but incompletely effective in treat-
ing electrographically confirmed seizures in neonates following cardiac surgery.
Given its more acceptable safety profile and potential noninferiority, leveti-
racetam may be a reasonable option for first-line therapy for treatment of sei-
zures in this population. Further prospective studies are needed to confirm these
results.

KEYWORDS
cardiology, congenital, critical care, heart diseases, infant

Wiley Periodicals, Inc.

© 2020 International League Against Epilepsy

Epilepsia. 2020;00:1–9.  |
wileyonlinelibrary.com/journal/epi     1
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2      THIBAULT et al.
1  |   IN TRO D U C T ION
Neonates with congenital heart disease (CHD) undergoing
cardiac surgery with cardiopulmonary bypass (CPB) are at
risk for seizures, with a reported incidence ranging between
5% and 20%.1–7 The occurrence of postoperative seizures is
associated with in-hospital mortality and worse neurodevel-
opmental outcomes.1,8–10 Timely and effective management
of postoperative seizures may reduce seizure-induced sec-
ondary brain injury, yet the optimal antiseizure medication
(ASM) strategy to treat acute symptomatic seizures follow-
ing CHD surgery in newborns remains unknown.
Phenobarbital (PHB) has been used for more than a cen-
tury and is the traditional first-line ASM for neonatal sei-
zures.11 It is metabolized by the liver via cytochrome P450
and primarily excreted by the kidneys.12 PHB pharmacoki-
netics is notable for maturation-related changes in clearance
in the first months of life, auto-inducible clearance with use,
and numerous drug interactions.12,13 Prior studies in neonates,
including randomized controlled trials, have reported PHB
efficacy of 40%-50% for neonatal seizures, although success
rates as high as 72% have been reported.14–17 Levetiracetam
(LEV) is a newer ASM increasingly used to treat neonatal
seizures.18 A small fraction of the administered dose is me-
tabolized via nonhepatic pathways, whereas two-thirds is ex-
creted unchanged via the kidneys. LEV pharmacokinetics is
notable for a linear clearance influenced by renal function
and subject to maturation-related changes in the first weeks of
life, few drug interactions, and a wide therapeutic index.19,20
Its efficacy in controlling seizures in neonates has been re-
ported to be between 35% and 100%. However, the data are
derived from observational studies with small sample sizes,
and efficacy was not consistently assessed with continuous
electroencephalographic monitoring (cEEG), which is the
gold standard for neonatal seizure detection.17,21–25 To date,
studies have not established an optimal seizure management
strategy in neonates with CHD. Thus, we aimed to describe
the safety and efficacy of PHB and LEV in treating postop-
erative electrographically confirmed acute symptomatic sei-
zures in neonates with CHD.
2  |  M AT E R IA L S A N D ME T HODS
2.1  |  Patient population
This was a single-center retrospective study of consecu-
tive neonates (≤30 days of age, corrected gestational age ≤
44  weeks) with electrographically confirmed seizures fol-
lowing cardiac surgery from June 15, 2012 to December
31, 2018. Following implementation of routine 48-hour
cEEG in all neonates following cardiac surgery with CPB
as per the American Clinical Neurophysiology Society
Key Points
• Phenobarbital was associated with more adverse
events than levetiracetam
• Phenobarbital and levetiracetam were equally but
incompletely effective in treating neonatal sei-
zures following cardiac surgery
• Levetiracetam may be a reasonable option for
first-line treatment for seizures in this population
• Further prospective studies are needed to confirm
these results
recommendations,26 all patients were tracked in a clinical da-
tabase as part of a previously published quality improvement
project.1 Only neonates with EEG-confirmed postoperative
seizures were included in this study. Per our protocol, cEEG
was continued for at least 24 hours after electrographic sei-
zure cessation. This study was approved by the Children's
Hospital of Philadelphia Institutional Review Board.
2.2  |  Characterization of seizures and
response to treatment
For the purpose of this study, all EEG tracings were rein-
terpreted by a single electroencephalographer (S.L.M.).
Electrographic seizures were defined as sudden and abnor-
mal EEG events with a repetitive and evolving pattern with a
minimum 2-µV peak-to-peak voltage and duration of at least
10 seconds.27 Seizures were classified as EEG-only (subclini-
cal, nonconvulsive) if no clinical signs were observed by the
bedside provider or on video review, or electroclinical if a
clinical manifestation was associated with an ictal discharge.
Clinical-only seizures (ie, seizures lacking an electrographic
correlate) were not included. Seizures were further classi-
fied according to their frequency as: (1) rare (<5 seizures),
(2) occasional (5-10 seizures), (3) frequent (>10 seizures),
or (4) status epilepticus (summed duration of electrographic
seizures comprises >50% of a 1-hour epoch). Our institu-
tion had no standardized practice for seizure management in
neonates following cardiac surgery, and ASM choices were
made by the clinical team. Favorable response to treatment
was defined as (1) complete cessation of electrographic sei-
zures following ASM administration and (2) no administra-
tion of further ASMs for seizure control. If an ASM was
successful in terminating seizures but was discontinued for
safety concerns, then it was defined as effective. If ≥2 ASMs
were administered before seizure cessation, then the last ad-
ministered ASM was defined as effective, unless otherwise
specified in the medical record.
THIBAULT et al.
2.3  |  Data collection
We collected data including (1) patient demographics (ges-
tational age, birth weight, age at surgery), (2) surgery-re-
lated data (primary cardiac anomaly, procedure performed,
CPB, deep hypothermic circulatory arrest and aortic
cross-clamp times, extracorporeal membrane oxygena-
tion [ECMO] support while on cEEG), (3) seizure type
(EEG-only, electroclinical) and severity (status epilepticus
or not), and (4) ASM data (sequence of ASM administra-
tion, timing, dosing, duration of therapy, relationship to
electrographic seizure cessation, plasmatic concentrations
obtained for therapeutic drug monitoring as per standard
of care). Loading doses were defined as any ASM boluses
given with the intent of quickly reaching a therapeutic
steady state and ending seizures within the initial 72 hours
following seizure onset. The total loading amount was de-
fined as the sum of all loading doses received over 72 hours.
Maintenance doses were defined as scheduled doses aimed
to maintain a steady state. Peak PHB plasma concentra-
tions were defined as concentrations obtained 1-2  hours
following a loading dose. Because of their antiseizure
properties, data were also collected regarding concomitant
administration of midazolam and ketamine for sedation or
analgesia. Adverse events were defined as any untoward
event attributed to an ASM by the clinical team and docu-
mented in the medical record. Collected safety data were
limited to the presence or lack of a specific adverse event
as a dichotomous variable. Additionally, deaths occurring
during patient hospitalization were recorded, regardless of
suspected relationship to ASM use.
2.4  |  Statistical analysis
We performed statistical analysis using the software Stata
(v14.2). We reported summary statistics as medians and in-
terquartile ranges for continuous data and proportions for cat-
egorical data. Comparative statistics for neonates receiving
PHB versus LEV as first-line ASM therapy were performed
with Fisher exact test for categorical variables and Wilcoxon
rank-sum test for skewed continuous variables.
3  |   R E S U LTS
3.1  | Patient characteristics
During the study period, 700 neonates underwent cEEG
following cardiac surgery with CPB. Electrographic sei-
zures occurred in 8.4% of neonates (59 of 700), and 94.9%
of neonates (56 of 59) with seizures received ≥1 ASM.
Three neonates had only a single brief EEG-only seizure,
|
     3
and the clinical team decided treatment was not war-
ranted; these neonates were excluded from further analysis.
Among the 56 neonates who received ≥1 ASM, the median
gestational age, birth weight, and postnatal age at surgery
were 38 weeks (37-39), 3.2 kg (2.7-3.5), and 5 days (3-8),
respectively. Nineteen neonates (33.9%) were premature
(<37  weeks of gestational age). The underlying cardiac
anatomy was a single-ventricle defect in 55.4% of neonates
(31 of 56). The four most common procedures performed
were the Norwood (20 of 56; 35.7%), arterial switch (six of
56; 10.7%), systemic to pulmonary artery shunt (five of 56;
8.9%), and repair of truncus arteriosus (five of 56; 8.9%).
Fourteen neonates (25.0%) were on ECMO, with 43% (six
of 14) cannulated in the operating room and 57% (eight of
14) cannulated in the cardiac intensive care unit (CICU).
Seven neonates (seven of 14; 50.0%) were cannulated to
ECMO following a cardiac arrest, including two neonates
in the operating room (two of six; 33.3%) and five neonates
in the CICU (five of eight; 62.5%). The remaining patients
were electively cannulated. EEG-only seizures were pre-
sent in 98.2% of neonates with seizures (55 of 56), and
electroclinical seizures were present in 14.3% of neonates
with seizures (eight of 56). Status epilepticus occurred in
23.2% of neonates with seizures (13 of 56). Sixteen (29%)
neonates died during their hospitalization. None of the
deaths was considered to be related to ASM.
3.2  |  ASM administration as
first-line therapy
Among the neonates who were treated with ≥1 ASM,
55.3% (31 of 56) received PHB, 39.2% (22 of 56) received
LEV, 3.5% (two of 56) received lorazepam, and 1.8% (one
of 56) received ketamine as first-line therapy. Table 1 pro-
vides a comparison of the demographics and clinical char-
acteristics between neonates who received PHB or LEV as
first-line therapy. The two groups were similar in baseline
characteristics.
3.3  |  ASM adverse events
PHB was associated with more adverse events than LEV
(P = .006). Eight neonates (14.3%) experienced an adverse
event, and all adverse events were associated with PHB ad-
ministration. Among the 43 neonates who received PHB,
seven neonates (16.3%) had hypotension attributed to its use
that limited administration. One neonate (2.3%) was deeply
sedated and had respiratory depression requiring initiation
of noninvasive respiratory support. There was no associa-
tion between the presence of an adverse event and peak PHB
plasmatic concentrations (P = .67).
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4      THIBAULT et al.

T A B L E 1   Demographics and clinical

Phenobarbital, Levetiracetam, Total,
characteristics
n = 31 n = 22 P N = 53
Male, n (%) 20 (65%) 10 (45%) .26 33 (59%)
Gestational age, wk 38 (37-39) 38 (37-39) .49 38 (37-39)
Premature, n (%) 11 (35%) 8 (37%) 1.00 19 (34%)
Birth weight, kg 3.2 (2.9-3.5) 3.1 (2.3-3.5) .58 3.2 (2.7-3.5)
Age at surgery, d 5 (3-8) 4 (2-6) .38 5 (3-7.5)
Single ventricle, n 16 (52%) 12 (55%) 1.00 31 (55%)
(%)
Most common surgical procedure, n (%)
Norwood 11 (36%) 8 (36%) .41 20 (36%)
Arterial switch 3 (10%) 3 (14%) 6 (11%)
Systemic-PA 1 (3%) 3 (14%) 5 (9%)
shunt
Truncus arteriosus 1 (3%) 4 (18%) 5 (9%)
repair
CPB time, min 46 (39-62) 68 (45-89) .15 51 (41-85)
DHCA, n (%) 24 (77%) 13 (59%) .23 40 (71%)
DHCA time, min 45 (35-55) 41 (34-49) .46 43 (34-52)
ECMO, n (%) 10 (32%) 2 (9%) .09 14 (25%)
Concomitant midazolam infusion
n (%) 2 (6%) 2 (9%) .64 4 (7%)
Maximum 0.03 (0.02-0.04) 0.03 (0.03-0.03) 1.0 0.03
infusion rate, mg/ (0.02-0.04)
kg/h
Concomitant ketamine infusion
n (%) 2 (6%) 6 (27%) .05a  8 (14%)
Maximum 0.23 (0.15-0.3) 0.25 (0.15-0.3) .73 0.25 (0.15-0.3)
infusion rate, mg/
kg/h
Status epilepticus, 10 (32%) 3 (14%) .20 13 (23%)
n (%)
Time from 2.3 (1.5-4.1) 2.3 (1.9-5.2) .59 2.3 (1.7-4.2)
seizure to ASM
administration, h
Survived, n (%) 21 (68%) 16 (73%) .75 38 (68%)
Note.: Values are given as median (interquartile range) unless otherwise specified.
Abbreviations: ASM, antiseizure medication; CPB, cardiopulmonary bypass; DHCA, deep hypothermic
circulatory arrest; ECMO, extracorporeal membrane oxygenation; PA, pulmonary artery.
a
Statistically significant.

3.4  |  ASM efficacy
The control of electrographic seizures following first-line ASM
administration was similar in both groups; 18 neonates (58.1%)
responded to PHB and 12 neonates (54.5%) responded to LEV
(P = 1.0), as shown in Figure 1. In neonates who responded to
first-line ASM therapy, there was no difference in the time from
first ASM dose administration to seizure cessation between
PHB and LEV (5.2 hours [0.7-11.6]) vs (1.5 hours [0.4-7.4],
P = .35). Of the 13 patients who did not respond to PHB as
first-line therapy, 10 (76.9%) received LEV as second-line
therapy with seizure cessation in three (30.0%), one (7.7%) re-
ceived lorazepam with seizure cessation in none (0%), and one
(7.7%) received phenytoin with seizures cessation in none (0%).
One patient died and did not receive a second-line therapy after
not responding to PHB as first-line therapy. Two neonates who
maintained control of seizures with PHB were subsequently
transitioned to LEV by the clinical team for long-term use given
THIBAULT et al.
F I G U R E 1   Flowchart of neonates
receiving phenobarbital or levetiracetam as
first- and second-line therapy and outcomes
(N = 53)
its presumed better safety profile. The combined efficacy of
PHB when used as first- or second-line therapy following LEV
was 57.9%. Of the 10 patients who did not respond to initial
LEV therapy, seven (70.0%) received PHB as second-line ther-
apy with seizure cessation in four (57.1%), one (10%) received
phenytoin with seizure cessation in none (0%), and two (20%)
received lorazepam with seizure cessation in none (0%). The
combined efficacy of LEV when used as first- or second-line
therapy following PHB was 46.9%. LEV and PHB combined
(first- and second-line) efficacy was not different (P  =  .47).
LEV and PHB were also administered as third-line therapy
in four and three neonates, respectively. Excluding PHB and
LEV, other ASMs administered included lorazepam in six neo-
nates (10.7%), midazolam infusion in seven neonates (12.5%),
midazolam boluses in three neonates (5.4%), fosphenytoin in
four neonates (7.1%), phenytoin in two neonates (3.6%), and
ketamine as a combination of infusion and boluses in two neo-
nates (3.6%). Figure 1 summarizes outcomes for neonates who
received either PHB or LEV as first-line ASM. Figure S1 sum-
marizes outcomes for each ASM administered for the entire
cohort, including non-PHB/LEV first-line ASMs.
3.5  |  ASM dosing
Table 2 summarizes the dosing, treatment timing, and peak
concentrations for patients who received PHB or LEV as
first-line treatment. The time from seizure onset to first PHB
dose administration was shorter in PHB nonresponders than
responders (1.9 hours vs 2.9 hours, P = .005). The initial load-
ing dose was not different between PHB nonresponders and
responders (10 mg/kg [10-20] vs 20 mg/kg [10-20], P = .2).
First-line PHB nonresponders received significantly more
PHB boluses as loading dose than responders (4 [3-6] vs 2 [1-
2], P = .00). As a result, first-line PHB nonresponders received
a significantly higher total loading amount than responders
(47.8 mg/kg [30-50] vs 20 mg/kg [19.2-25], P = .005) over a
longer period of time (12.63 hours [11.00-30.22] vs 0.35 hours
[0-5.75], P  =  .003). There was no difference between the
|
     5
time from seizure onset to first LEV dose administration be-
tween nonresponders and responders (3.0 hours vs 2.2 hours,
P = .25). There was no difference in the LEV initial loading
dose amount, number of loading doses, total loading amount,
or time to administer all loading doses administered for first-
line LEV nonresponders and responders (initial loading dose:
32.5 mg/kg [20-50] vs 30 mg/kg [20-30], P = .54; number of
doses: 1.5 [1-2] vs 1 [1-1.5], P = .55; total loading amount:
50 mg/kg [40-60] vs 30 mg/kg [20-50.5], P = .10; time to ad-
minister all loading doses: 0.33 hours [0-8.23] vs 0 hours [0-
2.75], P = .42). Neonates on ECMO received a higher PHB
total loading amount than neonates not supported by ECMO
(50 mg/kg [30-55] vs 25 mg/kg [20-40], P = .03). Similarly,
neonates with status epilepticus received a higher PHB total
loading amount than neonates with a lower seizure burden
(50 mg/kg [30-55] vs 25 mg/kg [20-46.4], P = .05). Neonates
with or without ECMO, and neonates with or without status
epilepticus, did not receive different LEV total loading amount
(ECMO: 44.6 mg/kg [20-69.1] and 45 mg/kg [30-51], P = .09;
status epilepticus: 50  mg/kg [40-60] vs 40  mg/kg [20-51],
P = .31). Of the 31 neonates who received PHB as first-line
therapy, 20 neonates (65%) had peak PHB levels drawn per
standard of care 1-2 hours following a loading dose. There was
no difference between maximum peak PHB concentrations in
neonates with or without favorable response to PHB first-line
therapy (29.4  mg/L [22.6-45.5] vs 40.1  mg/L [24.6-46.2],
P = .57), with or without ECMO support (24.6 mg/L [20.3-
43.1] vs 40.4 mg/L [27.7-45.7], P = .17), or with or without
status epilepticus (44.7 mg/L [24.6-47.1] vs 33.2 mg/L [22.6-
44.5], P = .19). LEV therapeutic levels were not routinely col-
lected as standard clinical care.
3.6  |  Concomitant medications during
loading dose administrations
Some neonates were administered medications with antisei-
zure properties for nonseizure purposes during the initial 72-
hour period following seizure onset. Midazolam infusions
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| THIBAULT et al.

T A B L E 2   Characteristics of phenobarbital and levetiracetam administration as first-line therapy

Responders, Nonresponders, Total,

Characteristics of administered doses n = 18 n = 13 P n = 31
Phenobarbital
Number of boluses 2 (1-2) 4 (3-6) .00a 2 (1-4)
Dosing of initial bolus, mg/kg 20 (10-20) 10 (10-20) .20 19.2 (10-20)
Dosing of additional boluses, mg/kg 10 (5-10) 10 (10-20) .06 10 (5-10)
a
Total dose received in first 72 h, mg/kg 20 (19.2-25) 47.8 (30-50) .005   30 (20-50)
a
Time from seizure onset to first dose, h 2.9 1.9 .005   2.3 (1.5-4.1)
Time from first dose to seizure 5.2 (0.7-11.6) — — —
termination, hb 
Maximum peak concentrations, mg/L 29.4 (22.6-45.5) 40.1 (24.6-46.2) .57 38.6 (23.7-45.6)

Responders, Nonresponders, Total,

n = 12 n = 10 P n = 22
Levetiracetam
Number of boluses 1 (1-1.5) 1.5 (1-2) .55 1 (1-2)
Dosing of initial bolus, mg/kg 30 (20-30) 32.5 (20-50) .54 30 (20-40)
Dosing of additional boluses, mg/kg 22.5 (20-48.8) 40 (25-50) .32 27.5 (20-50)
Total dose received in first 72 h, mg/kg 30 (20-50.5) 50 (40-60) .10 45 (30-51)
Time from seizure onset to first dose, h 2.2 3.0 .25 2.3 (1.9-5.2)
Time from first dose to seizure 1.5 (0.4-7.4) — — —
termination, hb 
Note.: Values are given as median (interquartile range) unless otherwise specified.
a
Statistically significant.
b
Time reported only if seizure stopped following first-line therapy.

were administered for sedation in 7% of neonates (four of 56)
at a maximum dose of 0.03 mg/kg/h (0.02-0.04). Ketamine
infusions were administered for sedation and analgesia in
14.3% (eight of 56) at a maximum dose of 0.25  mg/kg/h
(0.15-0.30). There was no difference in concomitant mida-
zolam infusions between neonates who received PHB or
LEV as first-line therapy (P = .64), whereas more neonates
who received LEV as first-line therapy received concomitant
low-dose ketamine infusion (six of 22 [27.3%] vs two of 31
[6.5%], P = .05). Concomitant ketamine or midazolam infu-
sions were not associated with more favorable response to
PHB (midazolam: P = .50, ketamine: P = 1.0) or LEV (mi-
dazolam: P = .46, ketamine: P = .65) as first-line therapies.
One (1.9%) patient received intermittent midazolam boluses
of 0.03 mg/kg/dose for sedation (total of 0.27 mg/kg admin-
istered over 43.05 hours). Boluses of ketamine and intermit-
tent doses of lorazepam were not administered for sedation
and analgesia.
3.7  |  Associated clinical features
Lower seizure burden (P = .001) and absence of ECMO
support (P  =  .002) were associated with favorable
response to first-line ASM administration. The pres-
ence of a single-ventricle defect was also associated
with decreased likelihood of response to first-line
ASM therapy (P  =  .01). There was no difference be-
tween time from seizure onset to first ASM administra-
tion between responders and nonresponders (P  =  .08).
There was no difference between the time from seizure
onset to first ASM administration between PHB and
LEV (2.32 hours [1.50-4.12] vs 2.27 hours [1.87-5.18],
P  =  .59). Cessation of seizures following administra-
tion of a first-line ASM was associated with survival to
discharge (86% in responders vs 52% in nonresponders;
P = .03).
PHB nonresponders were more likely to be on ECMO and
to have status epilepticus than responders (ECMO: eight of
13 [61.5%] vs two of 18 [11.1%], P = .006; status epilepticus:
nine of 13 [69%] vs one of 18 [5.6%], P = .00). The propor-
tion of single-ventricle defects did not differ between PHB
nonresponders and responders (nine of 13 [69%] vs seven of
18 [39%], P = .15). There was no difference in the propor-
tions of patients on ECMO or with status epilepticus between
the LEV nonresponders and responders (ECMO: two of 10
[20%] vs 0 of 12 [0%], P  =  .20; status epilepticus: two of
10 [20%] vs one of 12 [8%], P = .57). LEV nonresponders
THIBAULT et al.
were more likely to have a single-ventricle defect (eight of 10
[80%] vs four of 12 [33.3%], P = .04).
4  |   D IS C U SSION
Electrographic seizures occurred in 8.4% of neonates fol-
lowing cardiac surgery with CPB, consistent with published
literature.1,5,28 PHB and LEV were the most commonly ad-
ministered first-line ASMs. Seizures ceased after first-line
ASM therapy in about half of patients, consistent with previ-
ous studies in neonatal populations.14,15,17 Efficacy was not
associated with the choice of first-line ASM (PHB or LEV),
but it was associated with seizure burden and underlying dis-
ease severity. Factors associated with less favorable response
to first-line ASM therapy included ECMO exposure and sin-
gle-ventricle defects, which are both independently associ-
ated with an increased risk of seizures.2,29,30
PHB safety profile may limit its use in neonates following
cardiac surgery. Short-term adverse events, including hypo-
tension and respiratory depression, are concerning in patients
for whom hemodynamic instability frequently occurs concur-
rently with seizures. In our cohort, 16.3% of neonates who
received PHB had hypotension attributed to its use, although
this may be an underestimation due to the retrospective nature
of our study. To our knowledge, the incidence of hypotension
associated with PHB administration in neonates following car-
diac surgery has not been previously reported. However, up to
53% of neonates with hypoxic-ischemic encephalopathy were
prospectively found to have clinically significant hypotension
requiring inotropes after receiving PHB.31 Furthermore, neg-
ative long-term consequences associated with PHB use have
been described, including animal data indicating PHB-induced
synaptic changes and neuronal apoptosis in the neonatal
brain.32,33 LEV has not been associated with serious adverse
events in clinical studies.22,23,34–36 Moreover, it has not been
associated with cellular apoptosis in animal models.37,38
LEV could be considered as a first-line ASM given our
data indicating equal efficacy with PHB and a more favor-
able safety profile. Despite a lack of large prospective tri-
als, multiple small studies have demonstrated LEV efficacy
in neonates.17,21–25,35 Moreover, McHugh et al39 performed
a systematic review to compare the effectiveness of PHB to
LEV in a heterogenous cohort of neonates with seizures and
did not find any significant difference between the ASMs.
However, some factors need to be considered when inter-
preting our results. There was a nonsignificant trend toward
administering PHB first in status epilepticus. Similarly,
neonates who were more medically unstable seemed more
likely to receive PHB first, as suggested by a trend toward a
higher proportion of ECMO among neonates who received
PHB initially. These differences may reflect a clinician bias
toward using PHB for presumed difficult to treat seizures and
|
     7
LEV for less complicated clinical situations, and this may
have negatively impacted PHB success rate. Moreover, a
higher underlying illness burden may have contributed to the
increased incidence of adverse effect associated with PHB.
Although few neonates concomitantly received a ketamine
infusion, the proportion was higher among neonates who re-
ceived LEV as first-line ASM. Ketamine-LEV combination,
either through additive or synergistic effects, may have re-
sulted in greater antiseizure efficacy, thereby increasing the
LEV success rate.
Although our data did not indicate a better response rate
in patients with shorter duration between seizure onset and
treatment, faster ASM administration has been associated
with better outcomes in previous studies.40,41 Paradoxically,
PHB nonresponders had a shorter duration between seizures
and ASM administration in our study. We believe the benefi-
cial effect of prompt treatment may have been masked in the
current study because (1) PHB nonresponders were perceived
by the clinical team as more clinically unstable; and (2) PHB
nonresponders had more refractory seizures, as shown by the
greater proportions of status epilepticus in this cohort and a
trend toward more ECMO exposure. Better anticipation of
seizures in these high-risk patients may explain faster access
to medication, and the harder-to-treat nature of the seizures
may explain the lower treatment response.
Our study has several limitations. First, the size and ret-
rospective nature of our study may have prevented iden-
tification of specific subgroups who may have a better
response to a specific ASM (eg, neonates on ECMO). The
retrospective nature of our study also prevented us from
characterizing seizure burden with precision (ie, in min-
utes per hour). As this meaningful information was not col-
lected in our database, we had to rely on seizure frequency,
which is less informative. Second, the small sample size
may impact the ability to detect a small difference in effi-
cacy between PHB and LEV. We continue to collect stan-
dardized data on our cohort, which will allow continuous
assessment of efficacy in a larger cohort. Third, the optimal
PHB and LEV doses are not well defined in postoperative
neonates, and suboptimal ASM dosing in some neonates
may have led to reduced efficacy. PHB nonresponders re-
ceived significantly more loading doses and a higher PHB
total loading amount. This may reflect practice, in which
clinicians administer additional PHB loading doses to
nonresponders before initiating another ASM. However,
despite nonresponders receiving a higher total PHB load,
there were no significant differences in peak PHB levels
between neonates with or without a favorable response
to therapy, with or without ECMO exposure, and with or
without status epilepticus. This study was not designed to
characterize pharmacokinetic variability, and this observa-
tion is limited by very sparse sampling collected at differ-
ent time points. However, it suggests some interindividual
 |
8      THIBAULT et al.
variability that warrants further characterization. Fourth,
this was a single-center study of patients undergoing sur-
gical and postsurgical care provided by a limited number
of clinicians with relatively homogenous surgical strategies
and ASM selection. Future multicenter studies will provide
more generalizable data. Additionally, given that this group
of neonates is at high risk for structural brain abnormalities
secondary to acute brain injury, future assessments could
consider the role of neuroimaging abnormalities in treat-
ment response to ASMs.
In conclusion, in neonates with electrographically con-
firmed seizures following cardiac surgery with CPB, PHB and
LEV were equally but incompletely effective, with success
rates as a first-line ASM therapy of 58.1% and 54.5%, respec-
tively. Adverse events occurred more often among neonates
treated with PHB (14.3%) than LEV (0%). Because of its more
acceptable safety profile and potential noninferiority, LEV
may be a reasonable option for first-line therapy for seizures in
this population. Further prospective studies are needed.
ACKNOWLEDGMENTS
We thank the staff and research team at Children's Hospital
of Philadelphia for support of this study. This study was
supported with funds from the Endowed Chair of Cardiac
Critical Care Medicine. D.J.L. is supported by philan-
thropic support from the Steve and June Wolfson Family
trust and National Institutes of Health (NIH) grant funding
(NS-072338). N.S.A. is supported by NIH grant funding
(NS-096058).
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Journal's position on issues
involved in ethical publication and affirm that this report is
consistent with those guidelines.
AUTHOR CONTRIBUTIONS
C.T., S.L.M., and M.Y.N. wrote the manuscript; M.Y.N.,
S.L.M., N.S.A., D.J.L., and J.W.G. designed the research;
C.T. (primary author), S.L.M. (senior author), and M.Y.N.
(study principal investigator) acquired the data; R.X. ana-
lyzed the data (along with C.T. and S.L.M.).
ORCID
Céline Thibault  https://orcid.org/0000-0001-7612-2934
Maryam Y. Naim  https://orcid.org/0000-0002-9127-0043
Nicholas S. Abend  https://orcid.
org/0000-0001-6166-2663
Daniel J. Licht  https://orcid.org/0000-0002-4080-843X
Shavonne L. Massey  https://orcid.
org/0000-0002-8496-221X
J. William Gaynor  https://orcid.
org/0000-0001-7955-5604
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section.
How to cite this article: Thibault C, Naim MY,
Abend NS, et al. A retrospective comparison of
phenobarbital and levetiracetam for the treatment of
seizures following cardiac surgery in neonates.
Epilepsia. 2020;00:1–9. https://doi.org/10.1111/
epi.16469